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An Ovol2-Zeb1 EMT-Regulatory Circuit Governs Mammary Basal-Luminal Binary Differentiation

Abstract

The capacity of epithelial cells to acquire enhanced lineage plasticity could depend on their ability to undergo EMT. Investigations performed on cultured epithelial cells support a link between EMT and bestowment of stem cell (SC)-like properties, raising the possibility that regulators of EMT may be responsible for producing an intermediate cellular identity between epithelial and mesenchymal states and is compatible with SC potential. The goal of my thesis project is to identify and characterize key transcriptional regulators of the dynamic EMT process that facilitate the production and maintenance of epithelial SCs, using the MG as a model system. The Dai laboratory identified Ovol2 as a TF that is required for mammary and epidermal development. My work contributed to the discovery of Ovol2 as a master negative regulator of EMT that directly represses the expression of various EMT-related genes, the most important being Zeb1, a critical mediator of Ovol2 loss-of-function effects. Zeb1 is a potent EMT-TF implicated in conferring SC-like traits to differentiated cells in mammary epithelial tumors. However, its in vivo role within normal mammary epithelia has not been studied. I found that Zeb1 also directly represses Ovol2, leading to the identification of an Ovol2-Zeb1 cross-repression circuit, which is shown by mathematic modeling to support intermediate cellular states between terminal epithelial and mesenchymal identities. Additionally, my data shows that Zeb1 expression is activated during early pregnancy in the basal cells of the mammary epithelium, which are known to gain multipotency upon pregnancy or transplantation. Using in vivo and ex vivo approaches to determine how perturbations to the Ovol2-Zeb1 circuit regulate stemness, I found this circuit to be important in modulating mammary SC basal-luminal differentiation. In addition to protecting basal cells from precocious differentiation toward a luminal fate, Zeb1 functions in regulating SC self-renewal/proliferative activity. Both mechanisms may contribute to the observed, Zeb1 loss-induced defect in ductal branching during mammary regeneration. My findings uncover a previously unknown role of Zeb1 and its associated molecular circuit in regulating mammary SC activity and basal/luminal differentiation, offering new insights into how epithelial plasticity contributes to stemness and identify novel transcriptional regulators of epithelial SCs.

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